2PKS

Thrombin in complex with inhibitor

Summary for 2PKS

• Entry DOI: 10.2210/pdb2pks/pdb
• Descriptor: Thrombin light chain, Thrombin heavy chain fragment, Hirudin, ... (7 entities in total)
• Functional Keywords: inhibitor complex, thrombin inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734 P00734; Secreted: P28504
• Total number of polymer chains: 4
• Total formula weight: 33554.39

Authors

Xue, Y. (deposition date: 2007-04-18, release date: 2008-04-22, Last modification date: 2024-10-30)

Primary citation

Blomberg, D.,Fex, T.,Xue, Y.,Brickmann, K.,Kihlberg, J.
Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.
Org.Biomol.Chem., 5:2599-2605, 2007

PubMed Abstract: A series of 2,4-disubstituted pyridine derivatives has been designed, synthesised and evaluated as thrombin inhibitors. A Grignard exchange reaction was used to introduce various benzoyl substituents in position 4 of the pyridine ring, where they serve as P3 residues in binding to thrombin. In position 2 of the pyridine ring, a para-amidinobenzylamine moiety was incorporated as P1 residue by an SNAr reaction using ammonia as nucleophile followed by a reductive amination. A crystal structure obtained for one of the compounds in the active site of thrombin revealed that the basic amidine group of the inhibitor was anchored to Asp 189 at the bottom of the S1 pocket. A comparison with melagatran, bound in the active site of thrombin, revealed a good shape match but lack of hydrogen bonding possibilities in the S2-S3 region for the thrombin inhibitors reported in this study.

PubMed: 18019535
DOI: 10.1039/b705344d

Experimental method

X-RAY DIFFRACTION (2.5 Å)